Familial Alzheimer’s
Definition/Background Alzheimer's is considered familial when there is more than one person in a family that has been diagnosed with or is currently suffering from Alzheimer's. Familial Alzheimer's "usually implies multiple affected persons in more than one generation." (1) Familial Alzheimer's is extremely rare. In the population of those affected with the any form of Alzheimer's, less than 5% of cases are due to mutation in genes that determine the familial form of the disease. (2) This inherited form of the disorder manifests earlier in an individual's life than non-familial forms. Symptoms develop consistently before age 60 to 65 years and often before age 55 years". (1) Due to the younger ages of affected individuals, the disorder is more specifically labeled Early-Onset Familial Alzheimer's disease (EOFAD). Determining the Hereditability in 1991 (4) A 1991 article in American Journal of Human Genetics, studied linkage in chromosomes 19 and 21 for familial Alzheimer's. The authors set the division between late and early onset Alzheimer's at 60 years of age. At the time of the study, only 32 families were available to observe. The authors collected data in three ways: Family Data - collected blood, DNA Studies - obtained high-molecular weight DNA, and Linkage Studies. The data was then interpreted using APM, Two-Point LOD Score Analysis, Multipoint LOD analysis, and Heterogeneity analysis. The study concluded with evidence being found to support chromosome 19 linkage for late onset and chromosome 21 linkage for early onset. However, it is more important to note that at each stage in this experiment, uncertainty arises due to the minimal amounts of families that can participate in the study at this point in time. History In 1906, Dr. Alzheimer identified Alzheimer’s disease, which was named in his honor. Dr. Alzheimer had a patient for many years that suffered from “severe memory problems, confusion and difficulty understanding questions.” After the patient’s death, the doctor performed an autopsy and identified abnormalities that are now positive identification of Alzheimer’s disease. The abnormalities discovered included neuritic plaques and neurofibrillary tangles. (3) Phenotypic Effects (1) #Dementia #Beta-Amyloid plaque formation #Intraneuronal neurofibrillary tangles #Subtle memory failure that increases over time to become incapacitating #Confusion #Poor Judgment #Language Disturbance #Agitation #Withdrawal #Hallucinations #Seizures #Parkinsonian features #Increased muscle tone #Myoclonus #Incontinence #Mutism Affected Genes There are three genes involved with the inherited form of Alzheimer's: Amyloid Precursor Protein (APP), Presenilin-1 (PS-1), and Presenilin-2 (PS-2). The three genes collectively are termed deterministic genes because, if inherited, they ascertain that the disease will develop. (2) 'Amyloid Precursor Protein' The APP gene is located on chromosome 21 and was discovered in 1987. Mutations in this gene account for 10-15% of EOFAD cases. Mutations causing EOFAD in gene APP are predominantly missense or nonsense; they will largely occur in exons 16 and 17. Duplications in/of the APP gene are also a cause of EOFAD, but they only account for <1% of affected individuals with APP mutations. (1) 'Presenilin-1' The PS-1 gene is located on chromosome 14 and was discovered in 1992. Mutations in this gene account for 30-70% of EOFAD cases. The mutation in this gene that causes EOFAD is a 4555 base pair deletion in exon 9 or missense mutations in exon 9. Whole gene deletions are also possible mutations, but are extremely rare. (1) 'Presenilin-2' The PS-2 gene is located on chromosome 1 and was discovered in 1993. Mutations in this gene account for <5% of EOFAD cases. The mutations, that cause EOFAD, in the PS-2 gene are missense mutations. (1) Progression of Early-Onset Familial Alzheimer's by Gene 'APP' Patients with APP mutations experience symptoms usually beginning in their 40s-50s. Dementia is observed, which is a common indicator of Alzheimer's. Typical plaques and tangles are also experienced, as well as neuronal Lewy body inclusions. (1) Neuronal Lewy body inclusions are atypical masses of protein inside of nerve cells. 'PS-1' Onset occurs between ages 30-60, but is typically seen during a patient's 40s or 50s, and rarely occurs after age 65. Symptoms are said to progress at an aggressive rate in the next 6-7 years. Symptoms may include: language deficits, seizures, "spastic paraplegia with 'cotton wool' amyloid plaques", and myoclonus. (1) 'PS-2' PS-2 has the largest range for onset which ages from 40-75. The average duration of the disease is around 11 years. (1) Genotype-Phenotype Correlations (1) 'APP' *p.Ala692Gly Mutation: cerebral hemorrhage and presenile dementia *p.Ala673Val Mutations: (autosomal recessive) severe, typical plaque and tangle deposits and beta-amyloid deposition in the cerebellum *p.Gly693Gly Mutations: "enhanced beta amyloid protofibril formation and marked congophilic angiopathy *Locus Duplication: amyloid angiopathy and Lewy body pathology 'PS-1' *Mutations in Transmembrane Loops 2, 4, and 6: affects age of onset and duration *p.Leu113Pro and p.Val89Leu Mutations: frototemporal dementia *p.Leu392Pro and p.Met139Val Mutations: psychiatric symptoms at onset *Exon 9 Deletion: early spastic paraparesis *p.Met233Val and p.Tyr256Ser Mutations: very early onset with Lewy bodies Mode of Inheritance Familial Alzheimer's is inherited in an autosomal dominant manner. A child of an affected individual has a 50% of inheriting the mutation to cause the disease. If a pregnancy is believed to be at risk for inheriting the mutation, prenatal testing may be done. Testing Genetic testing may be completed in families with a history of EOFAD. However, not all individuals wish to know if they have the mutation. Many people in families with members affected choose not to be tested since a mutation means they will be affected. (5) Treatment *Individual treatment: includes treating seizures, hallucinations, sleeping problems, agitation, etc. *Assisted Living *Cholinergic Drugs (prevent fat deposits and aid in the movement of fat into cells) *Memantine: NMDA (glutamate) receptor antagonist *Physical and Occupational Therapy Resources #Bird, Thomas D. "Early-Onset Familial Alzheimer's Disease." National Center for Biotechnology Information. NCBI, 24 Sept. 1999. Web. 19 Oct. 2012. . ##Last updated October 18, 2012 #"What We Know Today About Alzheimer's Disease." Alzheimer's Association. Alzheimer's Association, 2012. Web. 16 Oct. 2012. . #"A History of Alzheimer's Disease." American Health Assistance Foundation. Alzheimer's Disease Research, 10 Oct. 2012. Web. 17 Oct. 2012. . #Pericak-Vance, M. A., Bebout, J. L., Gaskell Jr., P. C., Yamaoka, L. H, Hung, W. Y., Alberts, M. J., & Walker, A. P. (1991). Linkage studies in familial alzheimer disease: Evidence for chromosome 19 linkage. American Journal of Human Genetics, 48, ''1034-1050. #Alzheimer's Association. (2008, November). Genetic Testing. In ''Alzheimer's Association Research Center. Retrieved October 14, 2012. *Edits through 10/22/12 were completed by Lisz Graves